Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.
Cyril PottierFahri KüçükaliMatt BakerAnthony BatzlerGregory D JenkinsMarka van BlitterswijkCristina T VicenteWouter De CosterSarah WynantsPieter Van de WalleOwen A RossMelissa E MurrayJúlia FauraStephen J HaggartyJeroen Gj van RooijMerel O MolGing-Yuek Robin HsiungCaroline GraffLinn ÖijerstedtManuela NeumannYan AsmannShannon K McDonnellSaurabh BahetiKeith A JosephsJennifer L WhitwellKevin F BieniekLeah ForsbergHilary HeuerArgentina Lario LagoEthan G GeierJennifer S YokoyamaAlexis P OddiMargaret FlanaganQinwen MaoJohn R HodgesJohn B KwokKimiko Domoto-ReillyMatthis SynofzikCarlo WilkeChiadikaobi U OnyikeBradford C DickersonBret M EversBrittany N DuggerDavid G MunozJulia KeithLorne ZinmanEkaterina RogaevaEunRan SuhTamar GefenChangiz GeulaSandra WeintraubJanine Diehl-SchmidMartin R FarlowDieter EdbauerBryan K WoodruffRichard J CaselliLaura L Donker KaatEdward D HueyEric M ReimanSimon MeadAndrew KingSigrun RoeberAlissa L NanaNilufer Ertekin-TanerDavid S KnopmanRonald C PetersenLeonard PetrucelliRyan J UittiZbigniew K WszolekEliana Marisa RamosLea T GrinbergMaria Luisa Gorno TempiniHoward J RosenSalvatore SpinaOlivier PiguetMurray GrossmanJohn Q TrojanowskiDirk C KeeneJin Lee-WayJohannes PrudloDaniel H GeschwindRobert A RissmanCruchaga CarlosBernardino GhettiGlenda M HallidayThomas G BeachGeidy E SerranoThomas ArzbergerJochen HermsAdam L BoxerLawrence S HonigJean P VonsattelOscar L LopezJulia KoflerCharles L WhiteMarla GearingJonathan GlassJonathan D RohrerDavid J IrwinEdward B LeeVivianna Van DeerlinRudolph CastellaniMarsel M MesulamMaria C TartagliaElizabeth C FingerClaire TroakesSafa Al-SarrajBruce L MillerHarro SeelaarNeill R Graff-RadfordBradley F BoeveIan Ra MackenzieJohn C van SwietenWilliam W SeeleyKristel SleegersGourisankar GhoshJoanna M BiernackaRosa RademakersPublished in: medRxiv : the preprint server for health sciences (2024)
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
Keyphrases
- genome wide
- amyotrophic lateral sclerosis
- genome wide association study
- dna methylation
- risk factors
- copy number
- binding protein
- gene expression
- cerebral ischemia
- immune response
- cell proliferation
- risk assessment
- clinical trial
- climate change
- white matter
- multiple sclerosis
- subarachnoid hemorrhage
- circulating tumor
- single cell
- functional connectivity
- circulating tumor cells
- genome wide analysis